21-aminomethyl-pregnenes



3,033,873 7 ZI-AMINOMETHYL-PREGNENES United States Patent Ellis R. Pinson,-Jr., Waterford, Eugene J. A'gnello, Lyme,

and Gerald D. Laubacl1,.Niantic, Coma, assignors to Chas. Pfizer & Co., Inc., New York, N.Y., a corporation of Delaware v No Drawing. Filed May 11, 1960, Ser. No. 28,178

7 Claims. (Cl. 260-397.45)

This application is concerned with new and useful steroid compounds. More particularlyit is concerned with certain 17B-(fi-dialkyl amino)-propanoyl and 175- (fi-trialkyl ammonium halide-)-propanoyl derivatives of pregnenes which are usefulin the preparation of adrenocortically active steroids, the latter being characterized by the presence of a dihydroxylated propanoyl group at the .17B-position. These latter compounds are described 7 and claimed in copending and concurrently filed patent application, Serial Number 28,180.

The compounds of this invention .may be represented by the formula wherein R is a cyclopentanopolyhydrophenanthrene nucleus characterized by having adrenocortical activity when substituted at the 17B-position with an whydroxy acetyl group and M which is located at the 17B-position replacing the a-hydroxy acetyl group is either a fi-dialkyl ammonium propanoyl or a ,B-trialkyl ammonium halide propanoyl group.

The compounds of this invention may be further defined as compounds having the formula have been found to be useful as systemic and topical antiinflammatory agents. The compounds of this invention are useful in the preparation of compounds of this class.

The preferred compounds within the purview of this invention include those having the formulas:

3,033,873 I Patented May 8, 1962 In the above structures, R is hydrogen or methyl; R is hydrogen, fluorine, chlorine or methyl; R is hydrogen or hydroxyl; R is wherein R is an acyl group containing only carbon,

hydrogen and oxygen, beingderivedfrom mono or dicarboxylic acids containing up to ten carbon atoms; R

R R and Z have the same meaning as above; X is hydrogen, halogen, methoxy or ethoxy and Y isketo or ,B-hydroxyl. The water solubility of compounds derived from dicarboxylic acids is enhanced by conversion to alkali metal or alkaline earth metal salts by reaction with a suitable base such as sodium carbonate or calcium. hydroxide.

These salts are included the purview of this invention. In the preferred compounds represented above, the carbon atom at the lfi-position is always The epoxide is'converted to other halohydrins by reaction with a halogen acid or to an alkoxy compound by reaction with 72% perchloric acid in methyl or ethyl a1- cohol. The preparation of 9m-fluoro-A -hydrocortisone and the corresponding A -hydrocortisone by this procedure is set forth in detail by Fried et-al. in the Journal of the American Chemical Society, vol. 77, page 4181.

. A double bond at the 6(7 )-position can be introduced using chloranil in refluxing n-amyl alcohol or preferably tertiary butyl alcohol by the method of lAgnello and Laubach as set forth in the Journal of the American Chemical Society, vol. 79, page 1277. This procedure by whichadouble bond is introduced at the 6(7) position using a quinone having an oxidation-reduction potential less than 0.5 at a temperature between 70 C. and 190 C. in an inert organic solvent with a boiling point ofat least about 70 C. is also described and illustrated in United States Patent No. 2,836,607, issued July 27,

A- double bond can beintroduced at'the 1(2)-position by contacting the steroid compound with selenium dioxide in an inert organic solvent at an elevated temperature. Solvents which are useful for this :reactioninclude, for example, tertiary ,butanol, tertiary 'pentanol, benzene, ethylene glycol diethers such as dibutyl Cellosolve, the

, dipropylether of ethylene glycol and various other glycol ethers, phenetole, xylene, diox-ane and naphthalene. Preferred conditions include the addition of a lower aliphatic acid, particularly acetic acidto a tert-butanol mixture. In carrying out this reaction, it is generally preferred to utilizetemperatures of from about 75 f C. to about 200 C. for from about one hour to about one .hundred'hours. Generally, several-molecular proportions of selenium dioxiderare added during the reaction period. The application of this reaction is fully illustrated in copending patent application, Serial No. 672,550, filed August 18, 1957. It is also described by Meystre et al. in Helvetica Chimica Acta, vol. XXXIX, page 734.

Hydrocortisone and cortisone are typical 9-deshalo- A -1l-oxygenated-Zl-hydroxy compounds which are useful for the preparation of the valuableintermediates of this invention. They are well-known therapeutic agents which have been used for a number of years as antiinflammatory. agents. Hogg describes the preparation of 2 methyl hydrocortisone acetate and Z-methyl cortisone acetate in the Journal of the American Chemical Society,

m1; 77,ipage'6401. Spero et al. describe the corresponding .fi-methyl compounds and the 6-cbloro analogs are described by Ringolcl et al. in this same journal at vol. 78,

substituted with at least onehydrogen and at least three of R R R and the second substituent on the number sixteen carbon atom will always be hydrogen.

These compounds are preferred since by reactionsset forth more fully below, they are converted into the preferred adrenocortically active dihydroxylated' propanoyl steroid compounds described more fully in the aforesaid copending patent application,

Suitable starting materials for the preparation of the new'compounds of this invention include those steroid compounds such as hydrocortisone,,prednisolone,.A -hydrocortisone, Ber-fluorO. hydrocortisone, 16a-methyl prednisolone, 6a-fluorohydrocortisone and Z-methyl prednisolone,'all having an a-hydroxy acetyl group at the 17,8-

position. Other suitable starting compounds of this nature are well known or can be preparedby procedures 'known in the art.

fHalogen and alkoxy groups are introduced at the 9- position using the procedure of Fried and Sabo described A g in the Journal of the American Chemical Society, vol. 79,

'page 1130. This procedure involves dehydration of an ll-hydroxylated compound to give a M -compound with N-bromoacetamide. This compound is dehydrohaIQgenated to a 9,9,11p-epoxide with potassium acetate.

' 1 which is converted to a 9a,l1B-bromohydrin by reaction page 6213, and vol. 80, page '6464, respectively. United .StatesPatent No. 2,838,498, issued June 10, 1958, de-

scribed 6a-fluoro-hydrocortisone acetate. Shull et al. in

'United States Patent No. 2,745,784, issued May '15, 1956, describes 14ot-hydroxy hydrocortisone and l6a-hydroxy hydrocortisone is described in the Journal of the American Chemical Society, vol. 78, page 1909. The compounds 16fl-fiuorohydrocortisone and 16,8-fluoroprednisolone are 'described in copending patent application, Serial No.

850,032,1"1led November 11', 1959.

Compounds with 1'6-methyl substituents in'both the a and 13 configuration are known. The compound, 16amethyl cortisone acetate is characterized in the Journal of the American Chemical Society, vol. 80,page 3160,

and 16,8-methyl cortisonein vol. of this journal at volume '82, page 1250' (March starting compounds set forth above are example, an llfi-hydroxyl group is readily oxidized to an ll-keto group using chromium trioxide in acetic acid or the chromic-acid-pyridine complex. An l-l-keto group can be reduced to an 1 LB-hydroxyl group using lithium aluminum hydride or sodium borohydride. Both of these reagents aiford a mixture of llozand llB-epimers. The latter reagent is preferred since the product obtained is predominantly of the preferred .1.1,8-configuration. No matter which reagent is selected, however, there are well- .known means for separating the epimers- The Fried synthesis and/or the selenium dioxide or chloranil reactions of Agnello and Laubach are used to convert these known 9-deshalo-A -compounds to the 9-hal0- or 9-alkoxy-A A or A -2l-hydroxy compounds useful as starting materials for the preparation of .the compounds of this invention. In fact, many of these compounds .are known. For example, 6a-chloroprednisolone, '6a-chloro-9a-fluoroprednisolone acetate and 6a-c'nloro-9a-fluoroprednisone acetate are described in the Journal of the American Chemical Society, vol. 79, page 481-8.

As will be recognized by those skilled in the art, it may .be necessary to select the order in which certain of the reactions described above are applied to the preparation of the useful starting materials of this invention. Thus, for example, it is best to prepare 9a-fluorohydrocortisone and to then introduce the 14-hydroxyl group using the procedure of Shull et a1. since applicationof the Fried synthesis to a l4-hydroxylated compound would be com .plicated by simultaneous dehydration at the 9(11)- and l4,l-.positions. Similarly, it is necessary to protect a 16-hydroxyl group, for example, by acylation before oxidation of an *1 lB-hydroxyl group. 7

In the first step for the preparation of the valuable compounds of this invention, the 2l-hydroxy compounds are dehydroxylated at the 2l-position using p-toluene sulfonic acid and hydrogeniodide. This procedure is wellknown and is readily applied by first converting the 2l-hydroxy-l group to a tosyl ester and then reducing the compound so obtained with hydrogen iodide. The pro.- cedure is illustrated in the examples.

The 21-desoxy compound thus prepared is next treated with a mixture of a lower alkyl amine acid addition salt and formaldehyde, the latter conveniently provided as paraformaldehyde. The preferred amine salt is dimethyl amine hydrochloride. It is preferred because it is readily available at a relatively low price and because it gives good yields. However, other symmetrical and nonsymmetrical amine salts containing up to four carbon atoms in each alkyl group can be used. These include, for example, diethyl amine sulfate, methyl ethyl amine sulfate, di-n-butyl amine hydrobromide and ethyl is'o-' propyl amine hydriodide. It is preferred to utilize a hydrochloride salt, since these are usually the most readily available and give good yields. Further, it is sometimes desirable to add small amounts of acid before or during the reaction so as to maintain the pH of the reaction mixture at from about 2.5 to about 5. This is most conveniently accomplished with hydrochloric acid.

In carrying out the reaction, the reactants are mixed together in the selected solvent and maintained at a tem perature of from about 90 C. to about 140 C. for from about two to about twenty-four hours. The preferred solvents'for the reaction are alkanols containing up to five carbon atoms, although other lower aliphatic oxygenated solvents can be used. The preferred alkanols are n-propanol and n-butanol since they reflux at atmospheric pressure Within the preferred temperature range. Obviously, however, higher boiling solvents can be used, although usually not at the reflux temperature. Similarly, lower boiling solvents such as methyl and ethyl alcohol are useful if the reaction is carried out under pressure. It is generally most convenient to employ an excess of the paraldehyde and amine salt, to insure as complete a reaction as possible of the more expensive pregnene derivatives. ,An excess of from about 50% to about 600% or even more can be used.

The reaction will often be carried out in 'an inert atmosphere, .for example, a nitrogen atmosphere so as'to minimize loss of reaction product by side reactions. This, however, is not necessary.

At the end of the reaction period, the desired product may be isolated by evaporating the solvent, preferably in vacuo purified by triturating with hot dilute hydrochloric acid followed, 'in the case of compounds forming soluble hydrochlorides, with hot water. The water and dilute acid solutions are combined and made basic with dilute aqueous alkali, for example, 10% sodium carbonate, bicarbonate or similar reagent. Occasion l "the pure product will precipitate from the basic solution and may be recovered by filtration. If it does not precipitate, it may be extracted with a water immiscible lower hydrocarbon or halogenated hydrocarbon solvent such as ethylene chloride, chloroform, carbon tetrachloride, chlorobenzene, hexane or octane. The desired product is then recovered from the organic solvent by evaporation in vacuo. The extraction step may also beemployed with those products which precipitate from the alkaline solution and thus increase the overall yield.

In the case of compounds forming insoluble hydrochlorides, the residue from the trituration step is recovered by filtration and extracted with an organic solvent such as chloroform which dissolves the impurities. The hydrochloride is recovered by filtration and may be converted to the free base by treatment with dilute aqueous alkali as described above.

The quaternary lower alkyl ammonium halides of this invention are prepared from the foregoing amines by procedures usually employed for this purpose. Thus, for

example, the amine is mixed in a lower alkanol solvent, e.g. methanol or ethanol with an alkyl halide containing up to four carbon atoms and simply allowed to stand for from six to about sixteen hours at from about 20 C. to about 30 C. Usually an excess of as much as .fifty percent or more of alkyl halide will be used, but this is not essential. The solvent is removed, for example, by evaporation in vacuo and the product recovered as a residue. It may be purified by trituration with ether, acetone or other similar solvent. Methanol and ethanol are the preferred solvents for the reaction because of their good solubility characteristics and also because they can be readilyeva'porated due to their low boiling point. p

The preferred alkyl halides are methyl or ethyl bromide. These are preferred because they are the easiest to obtain and because at the temperature used, they are liquids. Other alkyl halides such as methyl or ethyl chloride can be used but they are usually less convenient since they are gases at ordinary temperature and pressure. Butyl bromide, methyl iodide, or isopropyl chloride may be em ployed. The iodides are generally not preferred because they form insoluble precipitates when the quaternary compound is decomposed to form the propenoyl compounds in accordance with the equations shown below. They can be used, however, and the product purified by repeated recrystallizations or by standard chromatographic procedures.

The compounds within the scope of this invention are usefulbecause they can be used directly without introducing a microbiological reaction to prepare therapeutically active compounds such as 9u-fluoro-2l-hydroxymethyln -pregnadiene-l 1,9, 1711,21-triol-3,20,-dione. Compounds of this .nature which are described and claimed in copending and concurrently filed patent application, Serial No. 28,180, are useful for the same purposes as hydrocortisone and prednisolone. They are prepared by treatment of the corresponding propenoyl compounds with osmium tetroxide. 'The1propenoyl compounds in turn are prepared from the compounds of this invention by treatment with water or dilute base. 7

The preparation of 2l-hydroxymethyl-A -pregnadienew rrant-moralmom cal dihydroxypropanoyl compound, is shown in the series ot reactions appearing before the examples.

one l 6 -hemisuccinate, Wm-

It should be mentioned'that compounds having two hydrogens' on the number two carbon atoms should be converted to 3-hydroxy compounds before they are reacted with formaldehyde and the selected amine. Otherwise, it is possible that a dialkylaminomethyl group will substitute at the 2-position as well as the 21-position. Subsequent to the formaldehyderarnine reaction, the ketone group can be regenerated using known oxidative procedures, for example, oxidation with chromic acid, and the double bond reintroduced at the 4-position by bromination followed by 'dehydrobromination inaccordance ,with known procedures.

One procedure which is especially useful in this respect :is that ofMancera et al described in the Journal of the American Chemical Society, 75, 1286 (1953); The cru- .cial step of this procedure is the selective reduction of the 3-keto group of an A-ring saturated steriod offthe SIS-series using sodium borohydride in pyridine. These authors have found that the selective reduction is possibleeven in the presence of ketone groups at the 11- and the 20-positi0ns. As adapted to the preparation of the compounds of this invention, the A-ring of a ,A -3-keto steroid is saturated by reaction with hydrogenin the presence of a palladium-charcoal catalyst. The 3-ketone group is then reduced using sodium borohydride in pyridine. Theresulting 3-hydroxy compound is treated with formaldehyde and an amine as described above.

'In an alternative. procedure, the 3-keto-A -steroid is converted to a 3-hydroxy-Ai-steroid by known procedures.

This compound is treated with formaldehyde and an 011 i To]:

dicarboxylieacids containing up toa total of ten carbon atoms. In the event that the acylated hydroxyl group isjderivecl from a dicarboxylic acid, it is often advantageous to treat the compound with a base derived from alkali'metal or alkaline earth metal to prepare a metal salt; These. bases include, for example, sodium, potassium, barium and calcium hydroxide as well as the corresponding carbonates and bicarbonates. Products so prepared are especially useful in the preparation of propenoyl compounds becauseof their increased solubility in water. 1

For the preparation of a l6-acylated compound, a 16- hydroxyl compound is esterified by treatment with an facidanhydride fora period of at. least six hours. For example, the acetate or hemisuccinate can be prepared by simply allowing the reactants to stand together overnight in a suitable solvent such as pyridine or pyridine in chloroform. p g

The compounds of thisinvention are converted to 1718- propenoyl compounds of which Compound V of the following synthetic outline is illustrative by reaction in an aqueoussolutionat a pH of from about 7 to about 12 at a temperatureof from about 20 C. to about 30 C. for a period of from about 1 to about 6 hours. The process and the compounds prepared by the process are described and claimed in copending and concurrently filed patent application, Serial No. 28,179. I

The propenoyl compounds are converted to 17,8-dihy- 'droxylated propanoyl compounds of the class illustrated by Compound VI of the following synthetic outline by reaction with osmium tetroxide in a lower ether solvent containing up to eight carbon atoms at a temperature of from about 20 C. to about 30 C, for a period of from about 16 to about 72 hours and decomposing the resulting osmate ester by bubbling hydrogen sulfide into the reaction mixture. 7 I The following pose of illustration and are not to be construed as limitations ofthis invention, many variations of which are possible Without departing from the spirit or scope thereof.

. 0H11- in, on;

0 --oH on i I (1) (H0110).

enema-H01 examples are given solely for the EXAMPLE I A -Pregnadiene-l J ,8,1'7c .-D il-3,20-D ione A total of 30 g. of A -pregnadiene-11p,17u,21-triol- 3,20-dione was dissolved in 175 m1. of pyridine in a 500 ml. three-neckedflask. The reaction mixture was maintained at approximately -25 C. and 19.1 g. of anhydrous p-toluenesulfonyl chloride in 200 ml. of methylene chloride was added dropwise with stirring. Stirring was continued for 16 hours and the reaction mixture was poured into a separatory funnel. The mixture was washed with 600 ml. of ice cold chloroform containing 100 ml. of water. The aqueous extract was removed and the chloroform layer was washed 4 times with 250 ml. portions of 2 N hydrochloric acid. The organic solution was then washed with aqueous sodium bicarbonate and then with water; It was dried over anhydrous sodium sulfate, filtered and the solvent removed invacuo to leave A -pregnadiene-l1p,17u,21-triol 3,20 dione 21-tosylate as a residue. e

The residue was taken up in 350 ml. of glac'ialacetic acid containing 26.9 g. of sodium iodide and refluxed with stirring for /2 hour in a nitrogen atmosphere. The solution was cooled and 200 ml. of 0.5 N sodium thiosulfate containing 2 g. of sodium bisulfite was added. The solvent was removed in vacuo using a rotating evaporator, heated by a steam bath and including a Dry-Ice-acetone trap in the train. The residue was diluted with 150 ml. of water. The precipitate was isolated by filtration and washing once with water and again with methanol. The light tan solid which was obtained weighed 15.5 g. and decomposed at 258 to 259 C.

All of the '21-desoxy compounds used in preparing the compounds of this invention are prepared by the foregoing method.

EXAMPLE II 2 1-Dimethylaminomethyl-A -Pregnadiene-l 1rd,] 70:-

' Dial-3,20-Di0n e A total of .50 g. of .A -pregnadiene-1 lfl,17cc-diOl-3,20 dione was taken up in 75.0 ml. of normal propanol containing 24 g. of para-formaldehyde, .80 g. of dimethyl amine hydrochloride and .3 m1. of dilute hydrochloric acid. The mixture was refluxed under nitrogen for 16 hours and the hot mixture filtered. The filtrate Was evaporated in vacuo and the residue digested in approximately 200 ml. of hot 0.25 N hydrochloric acid. The solid was removed by filtration and the filtrate adjusted to a pH value of approximately with aqueous 10% sodium carbonate. The solution was extracted with chloroform, the chloroform solution dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The precipitate was triturated with ethyl acetate and recrystallized twice from methyl alcohol. The analytical sample was recrystallized from approximately 10:1 ethyl acetate-ethanol and melted at 187 to 189 C.

CHBOH onon o=o Analysia-C H O N.-Calcd.: C, 71.78; H, :8.79; N, 3.49. Found: c, 71.68; H, 8.86; -N, 4.02.

EXAMPLE HI 21 -D imethy lam inomerhy l-M-Pregnene-I 1,8,1 7 wD iol- 3.,20-D ione A total of 25 g. of A pregnene-3p,11fl,17 r-triol-20-one was taken up in 350 ml. :ofmethanol containing 12 g. of

para-formaldehyle and 40 g. of dimethy'lamine hydro- EXAMPLE IV 21-Dimethylamin0methyl-2a-Methyl-A -Pregnene- 11p,l7a-Di0l-3,20-Di0ne A total of 35 g. of 2ot-methyl-A -preguene-1 1 [3,17a-di01- 3,20-dione was taken up in 500 ml. of n-amyl alcohol containing 20 g. of para-formaldehyde, 60 g. of dimethylamine hydrochloride and 2 ml. of dilute hydrochloric acid. The mixture was refluxed for 2 hours in a nitrogen atmosphere and filtered. The residue was digestedwith or hot 0.25 N hydrochloric acid and filtered. The filtrate was adjusted to anapproximate pH of 11 with 10% sodi- :um carbonate. The aqueous solution was extracted with ii-hexane. The hexane solution was dried over anhydrous magnesium sulfate, filtered and the desired product ob :tained by evaporating the solvent in vacuo.'

EXAMPLE V 9vc-Flu0J0-21 -D im'ezhy laminomethyl-A -Pregnadieize- 1 1,6,1 7a-Di0l-3,20-Dione A total of 10 g. of 9a-fiuoro-A #pregnadiene-11,8,17adiol-3,20-dione was taken up in 500 ml. of normal butanol containing 4.8 gx'of para-formaldehyde, 16 g". of dimethylamine hydrochloride .and 15 drops of 3 N hydrochloric acid. The solution was refluxed under nitrogen for 4 hours during which time an additional 1 ml. of 3 N hydrochloric acid was added to maintain the acidity at a pH of approximately 3. The solvent was removed in vacuo-and the residue digested with two 200 ml. portions of hot 0.25 N hydrochloric acid. The residue was washed with water, filtered, the filtrate made basic (pH approximately 10) with 10% aqueous sodium carbonate and extracted with benzene. The benzene solution was dried over anhydrous sodium sulfate, filtered and the solvent removed in vacuo to leave the desired product as a residue.

EXAMPLE VI 21-Methyl-EthylaminomethyLA fi Pregnadieue- 11fl-,17a-Di0l-3,20-Di0ne A was of 25 g. of A -pregnadiene-11B,17a-diol-3,20- dione was taken up in 350 ml. of methanol containing 12 a g. of para-formaldehyde and 40 g. of methyl ethylamine hydrochloride. The mixture was maintained at 100 C. under'pressure for 20 hours. The hot mixture was filtered and the solution evaporated in vacuo. The residue digested with hot 0.25 N hydrochloric acid, filtered and the filtrate made basic with Sodium carbonate. The solution was extracted with ethylene dichloride. The organic layer was dried over anhydrous sodium sulfate, filtered and the solvent removed in vacuo to leave the desired product as a residue.

EXAMPLE v11 7 9a-Fluoro-21-Dibutylaminomethyl-A -Pregnadienel1fl,17a-Di0l-3,20-Dione A total of 20 g. of 9a-fluoroaa -pregnadiene-l15,17-

diol-3,20-dione was taken up in 750 ml. of normal butanol containing 15 g. of para-formaldehyde, g. of dibutylaminehydrochloride and 15 drops of 3 N hydrochloric acid. The solution was refluxedv under nitrogen for 6 hours during which time an additional 1 ml. of 3 N hydrochloric acid was added and maintained the acidity at a pH of approximately 3. The solvent was removedin vacuo' and the residue digested with two 300 ml. portions of hot 0.25 N hydrochloric acid. The residue was washed with water, filtered 'and the filtrate adjusted to apH of approximately 10 with 10% aqueous sodium carbonate. 7

It was then extracted with chloroform. The chloroform solution was dried over anhydrous sodium sulfate, filtered and the solvent removed in vacuo to leave the desired product as a residue.

EXAMPLE VIII 21 -Dim'e thylan /iin 0methyl-6a-Me thyl-A -Pregnadiene- 11,8,17a-Di0l-3,20-Dione A total of g. of 6a-methyl-A -pregnadiene-115,17 adiol-3,20-dione was taken up in 500 ml. of butanol containiug 20 g. of para-formaldehyde, 60 g. of dimethylamine hydrohromide and 3 ml. of 40% aqueous hydrobromic acid. The mixture was refluxed for two hours and filtered. The filtrate was evaporated in vacuo and the residue digested with 150 ml. of hot 0.25 N hydrochloric acid and filtered. The filtrate was adjusted to an approximate pI-Iiof 10 with 10% sodium carbonate. The aqueous solution was extracted with carbon tetrachloride, the organic a I solution was dried over anhydrous magnesiumjsulfate;

filtered and the desired product obtained by removing the solvent in vacuo. 5 r

The new and useful compounds within the purview of a this invention form a large but determinable number.

The-following dimethylaminomethyl steroid compounds are illustrativeof the compounds of this invention which are preparedusing the processes set forth in the preceding examplesz" I l I I A -pregnadiene-l1B,14u,17a-triol-3,20-dione dione 6a-fluoro-A -f -pregnadiene-1 1B, 17a-diol-3,20-dione 6t-fluoro-9a-bIomo-A regnadieneJ15.14;,171-

triol-3,20-dione 6e fluoro-n -pregnadiene-17a-o1-3,1 1,20-trione 6u-fluoro-A -pregnene-1 1b, 16rx-di0l3,20-dl0116 oa-fluoro-M-pregnene-l 1 B, 16oz,17oz-[I'lOl-3,20'dl011e 6afl1101'0A -p1'eg11e116-16a, 17a-di0l-3, 1 1,20-trione 6e-fiuoIo-A -pregnadiene-115,1611, 17a-triol-3,20-dione 6a-fluoro-A t-pregnadiene-16a,17oc-diol-3,1 1,20-trione lGa-methyl-M-pregnene-l 1,8, 17a-diol-3,20-dione 16fi-methyl-A -pregnene-1 1fi,17a-diol-3,20-dione 16a-rnethyl-9a-bromo-A -pregnene-11B,17a-dio1-3,20-

dione 1 16B-methyl 9a-bromo-A -pregnene 1 1B, 17 a-diOl-3,20-

. dione 165-methyl-9u-fiuoro-a pregnene-11B,17u-diol-3,20-

dione V 16m-methy1-9a-fluoro-A -pregna diene-1 15,17ot-di0l- 3,20-dione V 6a-methyl-A -pregnadiene-1 1s, 17 a-diol-3,20-d ione Ga-methyI -A pregnene-17 -ol-3,11,20-trione 6 m-rn ethyl-Nd-pregnadiene- 17 oz-Ol-3, 1 1,20-trione 9c-fluoro-A -pre gnadiene 1 1p, 17a-diol-3,20-dione 9 a-fluoro-M-pregnene- 1 1fi,17a-diol-3,20-dione 9 uchloro-A -pregnene-1 1 ,8,17a-diol-3,20-dione 9u-bromo-A -pregnenel 1 p, 17a-diol-3,20-dione ,9og-iodo-A -pregnene-l1B,17q-diol-3,20-dioue I I 9a-methoxy-A -pregnene-1 1 18,17a-dio1-3,20-dione 9m-ethoxy-A -pregnene-1 15,17t-di0l-3 ,ZO-dione 9a.-fluoro-A -pregnene- 17 01-3 1 1,20 trione I 9oc-Cl1lQ1'0 -A -pregnene 1701-01-3 1 1,20-trione 9a-bromo-A -pregnene- 17a'-ol-3,'1 1,20-tr-ione 9m-iodo-A -pregnene-17a-ol-3, 1 1,20-trione 9a-methoxy-A -pregnene-1705-01-3, 1 1,20-trione 9a-ethoxy-A -pregnene-1711-01-3,11,2O-trione 3,20-dione V 3,2Q-dione 16,8-methyl 9u fliiormA -pregnadiene-1 15,17qdi0l- 3,20-dione 16a-methyl-9a-fluoro-A -pregnatriene-11fi,17u-dio1- 3,20-dine 6-methyl-A -pregnadiene-1 1fl,17a-diol-3,20-dione 6-methyl-A -pregnatriene-1 1fi,17a-diol-3,20-dione 6-rnethyl-A -pregnadiene-17a-ol-3, 1 1,20-trione 6-rnethyl-A -pregnatriene-17u-ol-3 1 1,20-trione 9u-fluoro-A -pregnadiene-1'15,17a-dio1-3,20-dione 9a-chloro-A -pregnadiene-1 1,8, l 7a-diol-3,20-dione 9a-bromo-A -pregnadiene-1 1 3, 17u-diol-3,20-dione 9u-iodo-a -pregnadiene-1 1 6, 17 a-diol-3,20-dione 9 x-methoxy-A -pregnadiene- 1 1B, 1 7oc-diOl-3, -dione 9a-ethoxy-A -pregnadiene-'1LB,17a-dio1-3,20-dione 9u-fluoro-A pregnadiene-17a-ol-3, 1 1,20-trione 9a-chloro-A -pregnadiene-17a-0l-3,l 1,20-tn'one 9a-bromo-A -pregnadiene-l7a-ol-3,l1,20-tri0ne 9alOd0-A -pIBgnadleH6-17a-0l-3,11,20-t1i0116 9a-methoxy-A -pregnadiene-17a-ol-3,11,20-trione 9a-ethoxy-A -pregnadiene-l 7a-ol-3,1 1,20-trione 9a-fluoro-A -pregnatriene-1 1B,17a-diol-3,20-dione 6-methyl-9or-fluoro-A epregnatriene-l113,17qz-di0l- 3,20-dione 6-methyl-9a-bromo-A -pregnatriene-1 173, '17oz-dl0l- 3,20-dione 6-methyl-9a-fluoro-A -pregnadiene l1B,17a-diol-3,20-

dione 6methyl-9m-bromo-A -pregnadiene-1 1,3,17a-(fi01- 3,20-dione 2a-methyl-A -pregnadiene-1 1}3,l7oc-diOl-3,20-di0116 2a-methyl-M -pregnadiene-17u-o1-3,1 1,20-trione 2a-methyl-9a-bromo-A -pregnadiene-1 1' 8, 17oz-Cli01- 3,20-dione 2a-methyl-9e-fiuoro-A -pregnadiene-llfi,17u-diol- 3,20-dione 2a-rnethyl-9a-fluoro-A pregnadiene-1711-01-3, 11,20-

trione 6a-c-hloro-A -pregnadiene- 1.1 p,.17a-diol-3, 20-dione 1'6u-fluoro-A -pregnadiene-1 1,6, l7a-diol-3,20-dione 9a,16e-difluoro-A -pregnadiene-11B,l7a-diol-3,20- dione 16fi-fluoro-A -pregnatriene-1 1 8, 1'7a-dio1-'3,20-dione 9a,16,8-difluoro-A -pregnadiene-1lB,17u-diol-3,20-dione EXAMPLE IX The above compounds are converted to lfioesters using standard procedures. The esters prepared include formates, acetates, propionates, butyrates, malonates, maleates, furnarates, hemisuccinates, hemiglutarates and decanoates. Those esters derived from dicarboxylic acids are converted to alkali metal and alkaline eanth metal salts by reaction with a molar proportion of a base such as sodium or potassium bicarbonate in accordance with procedures well known in the art.

EXAMPLE X 21-Dimethylaminqmethyl-A -Pregnadiene-I15,1 7a- Di0l-3,20-Dione Methobromide A solution of 7.5 g. of the compound prepared in EX- ample II in- 180 m1. of methanol and 80 ml. of methyl bromide is allowed to stand overnight and then evaporated to dryness in vacuo. The residue is triturated with acetone and the desired product recovered by filtration. An additional crop of the quaternary can be obtained by evaporation of the acetone filtrate and this is purified by trituration with methanol and recovered by filtration.

1'4 EXAMPLE XI ZI-Dimethylam inomethyl-M-Pregnene-I1,8,1 7nc-Di0l- 3,20-D-i0ne B utyl-Chloride A solution of 7.5 g. of the product obtained in Example 111 in ml. of ethanol containing a 50% molar excess of butyl chloride is allowed to stand at 25 C. for 16 hoursand then evaporated to dryness in vacuo. The residue is triturated with acetone and :the desired product recovered by filtration.

EXAMPLE .XII

21-DimethylaminomethyZ-Za-MethyI-M-Pregnene- 113,17a-Di0l-i20-Dione Diethiodide using the methods described in the last three examples.

What is claimed is: 1. A compound selected from the group consisting of those having the formulae:

I V V I I 7 JR, 7 6 R .15 j v i I 7 wherein R is selected from the group consisting of hydrogen and methyl; R is selected from the group consisting of hydrogen, fluorine, chlorine 'and methyl; R is selected from the group consisting of hydrogen and hydroxyl; R is selected from the group consisting of R is selected from the group consisting of hydrogen and acyl groups containing only carbon, hydrogen and oxygen and derived from monoand d-icavboxylic acids containing up to ten carbon atoms; R R and R are alkyl containing up to four carbons; X is selected from the group consisting of hydrogen, halogen, methoxy and ethoxy; Y is selected from the group consisting of keto and fl-hydroxyl; and Z is halogen.

2. 21 dimethylaminomethyl A pregnadiene 1118,

17u-diol-3,20-dione. V g Y 3. 21 dimethylaminomethyl A pregnene 115,17-

diol-SQO-dione.

s 4. 906 fluoro- ?.1 dimethylaminomethyl A preg- J nadiene-llfi,17a-d1o1-3,20-d1one.

7 5. 21 -'methy le'thylaminomethyl A pregnadiene- 1'1fi,17?di01'3,20'di011. 6. 21 dimethylanunomethyl 6c: methyl A preg- R4 nadiene-l1B,17a-diol-3,20-dione.

' 7. 21 1 dimethylaminomethyl A pregnadiene 11,8, R 17 a-dio1-3,20-dione methobromide. V

1 'y o l leference's' Cited in the file of this patent UNITED STATES PATENTS 7 2,552,194 Julian et 1. Y July 31, 1951 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF THOSE HAVING THE FORMULAE: 